Elsevier

Lung Cancer

Volume 67, Issue 3, March 2010, Pages 361-365
Lung Cancer

Increased serum kynurenine/tryptophan ratio correlates with disease progression in lung cancer

https://doi.org/10.1016/j.lungcan.2009.05.001Get rights and content

Abstract

Background

Indoleamine 2,3-dioxygenase (IDO) catalyzes the rate-limiting step of tryptophan (Trp) degradation along the kynurenine (Kyn) pathway. By depleting tryptophan, IDO is considered to be a fundamental immune escape mechanism for tumor cells. However, IDO expression in lung cancer has not been explored thoroughly. Thus, the present study investigated IDO activity determined by serum Trp and Kyn concentrations in lung cancer and the correlation between the IDO activity and clinical parameters.

Method

The concentrations of Trp and Kyn were measured simultaneously by liquid chromatography/electrospray ionization tandem mass spectrometry (LC–ESI/MS/MS) in the sera of 123 patients with lung cancer and 45 healthy controls. The IDO activity was estimated by calculating the serum Kyn-to-Trp ratio (Kyn/Trp ratio).

Results

Trp concentrations were significantly lower in patients with lung cancer than in healthy controls (62.6 ± 15.8 μM vs. 71.1 ± 11.8 μM, respectively; p = 0.0007), while Kyn concentrations were significantly higher in patients compared with the controls (2.82 ± 1.17 μM vs. 2.30 ± 0.56 μM, respectively; p = 0.0036). The IDO activity determined by the Kyn/Trp ratio was significantly higher in the patients than in the controls (47.1 ± 21.3 vs. 32.9 ± 9.10, respectively; p < 0.0001). In addition, patients in the advanced stages of lung cancer had significantly lower Trp concentrations and higher IDO activity than those in the early stages (p = 0.0058 and p = 0.0209, respectively).

Conclusions

IDO activity was increased in lung cancer patients, and higher IDO activity was associated with more advanced stages. These results suggest that increased IDO activity is involved in disease progression of lung cancer, possibly through its immunosuppressive effect.

Introduction

The immune system is highly specialized to recognize non-self-pathogens or tissues and efficiently eliminate them, but tumors can often escape host immunity in various ways. Accumulating evidence in tumor immunology has revealed that tumors generate an immunosuppressive microenvironment that protects the tumor from host immunity, promotes tumor growth, and attenuates immunotherapeutic efficacy [1], [2]. The molecular mechanisms underlying tumor-induced immunosuppression include the generation of regulatory T cells (Treg), impairment of dendritic cell (DC) function, and production of immunosuppressive cytokines, such as IL-10 and TGF-β [1]. More recently, indoleamine 2,3-dioxygenase (IDO), a tryptophan (Trp)-catabolizing enzyme, has attracted special attention in tumor-induced immunosuppression [3], [4], [5], [6], [7], [8], [9]. IDO catalyzes the rate-limiting step of Trp degradation along the kynurenine (Kyn) pathway [5]. Both the reduction in local Trp concentration and production of immunomodulatory Trp metabolites, such as Kyn, by IDO activity potently inhibit T cell proliferation and induce T cell apoptosis, leading to immune tolerance. Surprisingly, recent studies have demonstrated IDO expression in cancer cells as well as tumor-infiltrating antigen-presenting cells (APCs) in tumor tissues, indicating that this molecule is essential for the immune escape of tumor cells [4], [6], [10]. Indeed, IDO expression by tumor cells has been shown to correlate with a poor prognosis in several types of cancers [7], [8], [9].

Recent advances in mass spectrometry enable the simultaneous measurement of Trp and Kyn in human serum or plasma using liquid chromatography/electrospray ionization tandem mass spectrometry (LC–ESI/MS/MS). In human serum or plasma, the IDO activity can be estimated by the Kyn-to-Trp ratio (Kyn/Trp ratio), because Kyn is the first product formed through catabolizing Trp, which is tightly regulated by IDO. To date, several studies have shown that the Kyn/Trp ratio increases in the serum or plasma of patients with cancers, such as malignant melanoma [11] and gynecological cancers [12], suggesting that enhanced IDO activity play a role in immunosuppression observed in cancer patients. However, no data are available about the IDO activity determined from the Kyn/Trp ratio in serum of lung cancer patients using LC–ESI/MS/MS. The present study measured the serum concentrations of Trp and Kyn by LC–ESI/MS/MS and estimated the IDO activity in lung cancer patients. In addition, the correlation between the IDO activity and the clinical parameters of the patients was examined.

Section snippets

Subjects

One hundred and thirty-six patients with histologically confirmed primary lung cancer were referred to our institutions from 2002 to 2008. Among them, 13 patients were excluded because of chronic renal failure, which increased the serum Kyn/Trp ratio [13], and concomitant cancer other than lung cancers. Thus, a total 123 patients with lung cancer (99 men and 24 women with a mean age of 66.4 ± 10.1 years) were enrolled in the present study. No patients had autoimmune diseases, viral hepatitis, or

Clinical characteristics

The clinical characteristics of the 123 patients with lung cancer and 45 healthy controls are summarized in Table 1. Twenty six patients were classified as early lung cancer, and 97 patients were classified as advanced lung cancer. One hundred and nine patients had non-small cell carcinoma (72 adenocarcinoma, 23 squamous cell carcinoma, 4 large cell carcinoma, 3 adenosquamous cell carcinoma, 7 unclassified carcinoma), while 14 patients had small cell carcinoma.

Serum concentrations of Trp and Kyn

Concentrations of Trp, Kyn, and

Discussion

The present study simultaneously measured the serum concentrations of Trp and Kyn using LC–ESI/MS/MS and calculated the Kyn/Trp ratio to determine the IDO activity in patients with lung cancer. It was found that patients with lung cancer had significantly lower Trp concentrations and higher Kyn concentrations than healthy controls, resulting in significantly higher IDO activity. Moreover, degradation of Trp and increased levels of the IDO activity correlated with disease progression. These data

Conflict of interest

All authors have no conflicts of interest to disclose.

References (23)

  • K. Ino et al.

    Indoleamine 2,3-dioxygenase is a novel prognostic indicator for endometrial cancer

    Br J Cancer

    (2006)
  • Cited by (203)

    • Engineering metabolism to modulate immunity

      2024, Advanced Drug Delivery Reviews
    View all citing articles on Scopus
    View full text